Aging and dementia are typically associated with off-kilter circadian rhythms, with more than 80 percent of the 65-plus age bracket suffering sleep problems (Foley et al., 1995). Behavioral symptoms such as insomnia and agitation are two of the main reasons caregivers cite when they place their loved ones in institutions (Pollak et al., 1990; Pollak et al., 1991).

But the existence of “sundowning syndrome,” as the late-day anxiety is called, has been controversial. It could be that people who have trouble communicating release a day’s worth of pent-up frustration as night approaches. Or, caretakers and nurses might perceive their charges as more disruptive when the carers themselves are tired and cranky at the end of the day. Finding evidence of “sunupping” in mice nearing night’s end suggests sundowning is a real, biological phenomenon, said first author Tracy Bedrosian, who led the study with senior author Randy Nelson at the Ohio State University Medical Center in Columbus.

To examine sunupping in mice, Bedrosian had to become somewhat nocturnal herself, observing the mice as their lights-on time—2:00 a.m.—approached. She used two tests to measure activity and anxiety. For activity, the animals’ cages were equipped with light beams; the machinery counted every time a mouse crossed a beam. For anxiety, Bedrosian put the mice in a maze with covered and open sections; mice that did not mind being out in the open were, presumably, less anxious than those hiding.

In one group of experiments, the researchers compared seven-month-old, middle-aged mice with 29-month-old seniors (comparable to an 80-year-old person). Early in their nighttime, between 5:00 and 6:00 p.m., the different age groups were similarly active in their cages and equivalently anxious in the maze. But as the end of darkness neared, between 11:00 p.m. and midnight, the older animals moved about more, and spent less time in the open areas of the maze, than their younger counterparts.

Next, the scientists looked for a biological basis for the altered activity. Disruption of the cholinergic system is associated with dementia and circadian changes, and blocking acetylcholine receptors causes anxiety in rodents (Smythe et al., 1998). Bedrosian fixed brain samples and compared acetylcholinesterase staining in the nucleus basis of Meynert, the site of maximal cholinergic neuron degeneration in people with AD. In the middle-aged mice, the amount of staining was similar between the early and late time points. In the older animals, acetylcholinesterase staining nearly doubled between the early and late times. Since acetylcholinesterases degrade acetylcholine, this would result in less of the transmitter, leading to amped-up anxiety.

Finally, Bedrosian repeated her experiments with nine-month-old AD model mice expressing mutant human amyloid precursor protein. These mice were more active throughout the night, and more anxious late, than wild-type nine-month-olds.

There are no standard treatments for sundowning, Bedrosian said, because scientists do not comprehend what happens in the brain as bedtime nears. “This paper provides a mechanistic insight,” said Phyllis Zee of the Northwestern University Feinberg School of Medicine in Chicago, Illinois. “Work like this could lead to more targeted strategies.” Zee added that circadian alterations might contribute not only to sundowning, but also to cognitive and memory problems.

Cholinesterase inhibitors are already approved as a treatment for Alzheimer’s. “Our data suggest it might have an effect on sundowning as well,” Bedrosian said. The researchers also tried melatonin treatment in the mice, with little effect. The addition of light and dark therapy might be more effective, Zee suggested. In people with AD, melatonin and light therapy seem to work best in tandem (see ARF related news story on Riemersma-van der Lek et al., 2008; Dowling et al., 2008).—Amber Dance.

Reference:
Bedrosian TA, Harring KL, Weil ZM, Nelson RJ. Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice. Proc Natl Acad Sci U S A. 2011 Jun 27. Abstract